Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors

Abstract

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.

Chart 1. Selective SIRT2 Inhibitors

Chart 2. Putative SIRT1 Activators

Figure 1

Inhibition of SIRT2-mediated deacetylation reactions by compound 1a. (A) Western blot analysis of the inhibition of SIRT2-mediated α-tubulin deacetylation by 1a. The concentration of 1a was 200 μM, and measurements were performed at 30 min and 1 h. (B) Inhibition by 1a of the SIRT2-mediated deacetylation of the acetylated peptide RSTGGK(Ac)APRKQ. The reaction was detected by formation of the reaction product ¹⁴C-nicotinamide.

Scheme 1. General Methods for the Syntheses of Compounds 1a–p, 2, 3a,b, and 4–6

Reagents and conditions: (a) appropriate aldehyde, DIPA, EtOH, MW, 160–170 °C, 1 h, 17–88%; (b) Py·Br₃, CH₂Cl₂, room temp, 2.5 h, 81%, cis/trans ratio 80:20; (c) CaCO₃, DMF, MW, 100 °C, 20 min, 84%; (d) i. benzoyl chloride, pyridine, room temp, 2 h; ii. KOH, pyridine, 50 °C, 4 h; iii. HCl, AcOH, reflux, 14 h, 89% (over three steps); (e) NaBH₄, MeOH/THF, 0 °C→rt, 15 min, 98%, 95:5 ratio of diastereomers; (f) Et₃SiH, BF₃·Et₂O, CH₂Cl₂, −78 °C→rt, 19 h, 44%; (g) p-TSA (cat.), MgSO₄, toluene, 90 °C, 1.5 h, 63%.

Figure 2

Structures used for the DFT calculations of VCD spectra used to determine the absolute configuration of the enantiomers of 1a. To simplify the ab initio calculations, the 2-pentyl group in 1a was truncated to an ethyl group.

Figure 3

Comparison of the experimental VCD spectra of (−)-1a (blue) and (+)-1a (green) with the calculated spectra of the S-enantiomer (purple) and the R-enantiomer (red) of 8-bromo-6-chloro-2-ethylchroman-4-one, respectively.